The long-term goal of this project is to elucidate molecular mechanisms that regulate cell-cell communication during development. We are interested in two related key questions in cellular communication: 1) how are tissues patterned and correctly connected by long-range signals, and 2) how are cells structures and functions coordinated at short-range with those of their neighbors. We study these processes by focusing on early developmental patterning, and on development of a specialized cell-cell interaction zone, the neuromuscular junction (NMJ). Bone morphogenetic proteins (BMPs) function at both long-range and at short-range to accomplish diverse patterning control. We have previously revealed how evolutionary changes in proteolytic control of BMP binding proteins affect the function of multi-molecular BMP shuttles critical for the formation and function of morphogen gradients. These processes impact the early stages of embryogenesis across the animal kingdom. BMPs are also utilized to modulate growth, development and homeostasis at the Drosophila NMJ, a glutamatergic synapse similar in structure and function to vertebrate central excitatory synapses. In flies each NMJ is unique and identifiable, synapses are large and accessible for electrophysiological and optical analysis, making the Drosophila NMJ a favorite genetic system to study synapse development. At the Drosophila NMJ, Glass bottom boat (Gbb), a BMP-type ligand secreted by the muscle, provides a retrograde signal that promotes synaptic growth and confers synaptic homeostasis. Gbb signals by binding to a presynaptic hetero-tetrameric complex of type-I and type-II receptors. Activated receptors recruit and phosphorylate the BMP pathway effector, Mad. Phosphorylated Mad (pMad) accumulates at two locations: in the motor neuron nuclei (nuclear pMad) and at the NMJ synapses (synaptic pMad). Nuclear pMad, in conjunction with transcription factors, modulates expression of target genes important for synapse growth and function; a role for synaptic pMad remains to be determined. We discovered that pMad signals are selectively lost at NMJ synapses with reduced postsynaptic glutamate receptors. Specifically, loss of a particular receptor subtype (type-A glutamate receptors) induced complete loss of synaptic pMad signals. In contrast, nuclear pMad persisted in motor neuron nuclei, and expression of BMP target genes was unaffected, indicating a specific impairment in the pMad production/ maintenance at synaptic terminals. Furthermore, synaptic pMad accumulation followed the activity (quantal size) and not the net levels of postsynaptic type-A receptors. Synaptic pMad appears to function as a local sensor for NMJ synapse activity and has the potential to coordinate synapse activity status with an instructive BMP retrograde signal required for synapse growth, stability and homeostasis. The molecular mechanisms underlying the ability of synaptic pMad to function as an acute sensor for postsynaptic activity are currently investigated.